JPS6092274A - Manufacture of 5-substituted pyrimidine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION LLL Starvation Pressure No. 1 The present invention relates to a novel method for synthesizing 5-substituted pyrimidine compounds.

[LlE It is well known in the technical field that 5-halopyrimidine compounds are difficult to react in nuclear substitution reactions (T11e
Chcmister of l-1eteroc cl
ic3-2-technical and μm"13λ"1"]ko"-βyu,
D, , ノ, Brown, 2
) (J-j■Jβ-VR1-1-1 and O3Chapte
r IX, C, 1nterscience publ
isl)ers (1962)). Usually, the substitution reaction of the halogen atom at the 5-position of the pyrimidine ring is carried out at normal pressure and high pressure for a long time, but the success rate is often only moderate.

"Small" 1 U and as well.

The present invention provides a simple and economical nuclear substitution reaction of 5-chloropyrimidine and 5-bromopyrimidine analogs. According to the method of the present invention, the reaction time can be significantly shortened compared to conventional methods, and the substitution reaction can be carried out at a much lower temperature. Moreover, the yield appears to increase depending on the nuclear reagent used in the synthesis reaction.

The method of the present invention is based on the formula (■): (wherein R1 is C1-C6 alkyl or phenyl, R
2 is -NH2, -Nl-IcI-1a, -N-(C
H3) '2 or C1-C6 alkoxy, m represents O-3 1) A novel method for producing a 5-substituted pyrimidine represented by the formula (■): (wherein, X is bromo or chloro and R1 and I
has the same meaning as above) and a suitable nuclear reagent,
The method comprises carrying out the reaction under pressure in the presence of a catalytically sufficient amount of copper catalyst within a temperature range of about 0 DEG C. to about 200 DEG C. for about 10 to 90 minutes.

As used herein, the phrase 01-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. Typical C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 5ec
-butyl, t-butyl, isobutyl, n-pendel, isopentyl, n-he4:sil and the like.

In addition, the phrase C1-C6 alkoxy means a carbon atom number of 1
Refers to ~6 straight or branched alkoxy groups. Representative C1-C6 alkoxys include methoxy, ethoxy, n-propoxy, n-butoxy, neopentoxy,
Includes n-hexoxy and the like.

It is certain that all of the various methods disclosed in this specification are useful, but among the methods of the present invention, the following methods are preferred. That is, as shown in the above formula, X is bromine, m is 0, and R2 is -NH.
Preference is given to CHa, -N(CH3)2 or especially -N1'2. Other preferable reaction conditions will be described later.

The method of the present invention is carried out by contacting a 5-halopyrimidine with a suitable nucleophile under the following conditions. As used herein, the phrase "a suitable nucleophile" refers to a pyrimidine. Refers to a reagent capable of replacing a halogen atom of the starting material (IT) to give a product of formula (I). Representative examples of such nuclear reagents include ammonia, monomethylamine, dimethylamine, or alkali metal 01-C
6 alkoxide derivatives. Typical alkali metals are lithium and potassium, with sodium to lithium being preferred. These alkali metal 01-C6 alkoxide reagents are either commercially available or easily prepared by mixing the desired alkali metal and an appropriate alcohol under standard reaction conditions. can do. All nitrogen-containing nucleophiles are commercially available.

6-reaction) Depletion of the nuclear reagent present in the compound is not critical, and an excess amount is generally used.When using an amine as a nuclear reagent, the hydrogen chloride or hydrogen bromide M salt produced by the reaction is usually [Use an amine with sufficient suspension of J. Therefore, in the method of the present invention, 1 to 10 parts of nuclear fil'7'l is usually used. Although various protic solvents such as alcohols can be used in this reaction, water is a particularly excellent solvent.When using C1.~06 alkoxide derivatives of alkali metals as the nuclear reagent,
Methanol or ethanol are preferred solvents, and approximately equal amounts of nuclear reagents may be used.

The process of the invention also requires a catalytically sufficient copper catalyst. As used herein, the phrase "catalytically sufficient enhancement" refers to an amount of copper catalyst that can increase the reaction rate. The amount of catalyst present in the reaction mixture is generally less than that of the reactants, ranging from about 0.01% to about 15.0% relative to the starting 5-heropyrimidine (IT). be able to.

If desired, more catalysts can be used, but this does not seem to have any effect on the operability of the reaction. Any copper catalyst can be used as a catalyst, but metal Copper, cuprous chloride, cupric dihydride, cupric nitrate, and cupric sulfate are preferred.

The process of the invention is carried out in a reaction vessel or autoclave that can withstand high pressures. The type of reaction vessel is not critical to the operability of the reaction. Glass or resinous 1-crepe can withstand pressures up to about 60 psi, although stainless steel containers are preferred because they can withstand higher pressures. The reaction components are placed in an autoclave such that air pockets 1~ are removed when the container is sealed. It is preferable to equip the vessel with a means for stirring the reaction components and to operate this stirring means.Also, the reaction vessel may be provided with a heat source such as a thermal jacket.

The reaction is carried out at a temperature of approximately 0°C to approximately 175°C, but
The range is preferably from 0°C to 150°C, and about 40°C to about 14°C.
A range of 5°C is particularly preferred. As the temperature in the reaction vessel increases, the pressure also increases according to the formula: Here, n is the number of moles of 5-heropyrimidine, R is the gas constant, and V is the volume of the reaction vessel, which are constant values.

Therefore, pressure (P) increases in proportion to increase in temperature (T). Generally the pressure will be in the range of about 30 psi to about 400 psi depending on the parameters listed above.

When the reaction is carried out as described above, the reaction takes place over a relatively short period of time, usually until the temperature of the reaction mixture reaches the desired range.
After c, the process will be completed in about 10 to 90 minutes.

Surprisingly, it has been found that as the reaction time increases, the product traps actually obtained decrease. for example,
At an optimal temperature of 140-145°C and a pressure of 200 psi, the reaction is essentially complete after about 30 minutes. The product is then isolated according to standard procedures. Usually, the reaction mixture is extracted by evaporation to dryness under reduced pressure, or when the reaction solvent is water, it is extracted with an organic solvent that is immiscible with water.

The organic layer is then evaporated to dryness and the resulting residual product is optionally crystallized from common solvents or purified by any of the purification methods using a solid support such as silica gel or alumina. Further refine the crab.

The compounds obtained according to the method of the invention are useful for various purposes. For example, U.S. Patent No. 4.323.5
No. 70 discloses certain substituted 5-aminopyrimidine derivatives as intermediates for compounds useful in high surface pressure therapy. US Patent Application No. 506,174 shows that the alkylation of aminopyrimidines obtained by the process of the invention gives compounds with fungicidal activity. The 5-alkoxypyrimidines obtained by the method of the present invention are dealkylated by standard methods to give hydroxy derivatives, and by esterifying this, compounds having insecticidal and acaricidal activities can be obtained (U.S. Pat. 4.127.'652).

In addition, N,N-dimethyl-5-pyrimidineamines obtained by the method of the present invention are useful for controlling coccidiosis in animals, and are therefore suitable for oral administration to diseased wh by mixing them in feed. It is a compound. The active substance is added to about 1 to about i
When administered at a rate of oooppm, preferably about 110-400 ppm, coccidiosis microorganisms are killed or their growth is significantly inhibited.

The 5-haf-1 pyrimidine compound, which is the starting material for the method of the present invention, can be obtained from a commercial product or can be easily produced by a known method. For example, U.S. Pat.
．． ．． No. 252,955 describes the treatment of formamide with 4-
It is taught that upon reaction with 8-day-5-di-droxy-2(5l-()furanone, 5-di[10- or 5-bromopyrimidine is obtained. Starting materials used in the process of the invention) For a comprehensive explanation of the synthesis of [The CI
remistrvoof Hetcrocyclic C
pounds, l), ,1, B row
nThe Pyrimidines, Chapter 2NO
Published by 2111terSCier+ce (1962),
1.

The method of the present invention will be explained in detail with reference to Examples below. These examples are not intended to limit the invention in any way.

Support 5-15-aminopyrimidine 5-bromopyrimidine 79', 50 (0,b mol),
Concentrated ammonium hydroxide 250πa J: and cupric sulfate 5
g (0,031 mol) in a stainless steel autoclave with a capacity of 500 (△111oclav
eEng! neerS, [r! e, pen
sllVania). The autoclave was sealed and surrounded by a thermal jacket. Approximately 2 stirrers
The reaction mixture was stirred by rotating at 0 rpm and heated slowly until after 29 minutes the temperature in the reaction vessel was 142° C. and the pressure was 200 psi. If the solution is allowed to react at that temperature for 15 minutes, the pressure will drop to 150 ρsi. Remove the heat source and allow the aqueous mixture to cool sufficiently after 71] L/10
Extracted three times with 0Iβ portions of diethyl ether.

The combined organic extracts were dried and filtered to obtain 3.3 g of pale yellow crystals. When this substance was analyzed by NMR, 4
It contained 7153 parts starting material/product material.

On the other hand, the aqueous layer was divided into two parts of 150πβ each. One half was subjected to a continuous liquid-liquid extractor using chloroform as a solvent. After 16 hours, the chloroform extract was filtered to collect a pale brown solid, yielding 14.3 (l) of 5-aminopyrimidine. After collecting the solid, the mother liquor was concentrated to dryness under reduced pressure.
Add 5.7 g of phase 5-aminopyrimidine. 5.7 g of the crude product thus obtained was slurried in about 2 Qijl of diethyl ether, filtered, washed with diethyl ether, and air-dried to give the purified 5-aminopyrimidine 4.43 (I). The remaining aqueous solution 150ffβ was processed in a continuous chloroform extractor for about 60 hours.Cold IJI
L. The crystallized product was collected by filtration to obtain 19 g of 5-aminopyrimidine 1z. The solution was again concentrated to dryness and slurried in diebur ether to give the product 3.86
(] was obtained. Therefore, a total of 37.49 (+) 5-aminopyrimidines were isolated (yield 79%).
rl = 170°C to 171°C IJI N, N-dimethyl-5-pyrimidineamine 5-bromopyrimidine 39.74] (0,25 mol
), anhydrous cupric sulfate 2.51 J (0,016 mol),
/IO% dimethylamine aqueous solution 1210.9a13- (1,875 mol) was added with water to make a total amount of 380,
The reaction mixture was placed in a stainless steel reaction vessel at 500πC. The reaction vessel was sealed and heated to approximately 113°C and 60°C.
Heat to psi for 30 minutes. The cooled reaction mixture was extracted three times with 100 yzE portions of diethyl ether.

The combined organic extracts were dried and evaporated to dryness under reduced pressure to yield 16.9 g of a material containing starting material and N,N-dimethyl-5-pyrimidineamine in a ratio of 95:5.

The aqueous layer was extracted with a continuous extractor using chloroform as a solvent for approximately 16 hours.
Time processed. The organic layer was separated, filtered and evaporated to give a clear amber oil. The aqueous layer was again subjected to a continuous extractor and treated for an additional 4 hours to recover 0.8o oil. Combine the two oily extracts for 2~
Vacuum distillation was carried out under a pressure of 3 mm. Both fractions distilled at 97 DEG to 103 DEG C. were collected to obtain 2.4 g (yield 7.8%) of N,N-dimethyl-5-pyrimidineamine.

LL11! iN-Methyl-5-pyrimidineamine A solution of 80 (0.5 mol) of 5-bromopyrimidine, 290 (3,74 mol) of a 14-40% aqueous monomethylamine solution and 50 (0,031 mol) of cupric sulfate was prepared. The reaction mixture was heated at about 1/'IO DEG C. for 1 hour. The pressure at the beginning of the reaction was 108 psi and at the end the pressure was 131 pSi.

The reaction mixture was cooled to room temperature and treated in a continuous extractor with RI[10 form as solvent for 16 hours. The precipitated solid was collected by filtration] Recrystallization from 1- toluene yielded N-methyl-5-pyrimidineamine 22.3 (+. Part of it was recrystallized from 1-toluene to give a yellowish brown color. A sword-like crystal was obtained (mp-95 to 98°C).The aqueous layer was diluted with chloroborm for about 1
After re-extracting for 6 hours and concentrating the organic layer under reduced pressure, a brown solid 23 was obtained.
゜79 is 1q. Total product yield is 50.5! ], and the yield is 92.7%. 1 crystallized from the first extract! A small amount of the product was applied to a silica gel column and dissolved with methanol. It was further purified using 11 ml. Dissolve the material collected from the column in a small amount of warm toluene, cool the solution, and collect the precipitated solid by filtration.
Yellowish brown crystals of N-methyl-5-pyrimidineamine were obtained. m+1 = 99°C to 100.2°C Elemental analysis (C5H7Na > CI-IN Theoretical value: 55,03 6.74 38.50 Actual value:
54.78 6.23 38.20:Utt:E 2
- t-Butyl-5-aminopyrimidine 2- t-butyl-5-bromopyrimidine 1.35! J
(0,006 mol), cupric sulfate 0.15a (0,
94 mol) OJ: warm ammonium hydroxide 200 cod,
The reaction was carried out for about 1 hour and 25 minutes at 150'C in an autoclave under stirring. The pressure of the reaction system at this point is 25
It was 0 psi. The reaction mixture was then cooled and heated to 50
% sodium hydroxide 3yβ was added to make the solution clear.

This material was extracted three times with 70πρ portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate.

Distillation under reduced pressure gave a light brown solid 0.95(). This material was recrystallized from hexane/ethyl acetate (90/10) to give the product 0.57()
5℃. Applying this material to a small silicon dioxide plug,
When dissolved with ethyl acetate/hexone (1/1) and dissolved in N1, the desired product was 0. /14o was 141 (mp=133℃～
136℃). When the electrolyte was put into a 50o silicon dioxide column and eluted with ethyl acetate, 0.04(l) of the target substance was obtained. Yield: 50%).

, uLii 5-Methoxypyrimidine A solution of 6.32 J (0,275 mol) of the metal sulfuric acid dissolved in 300 ym of methanol was mixed with 40 g (0,25 mol) of 5-bromopyrimidine and 2.5 mol of cupric sulfate.
+ (0,016 mol) in methanol 100πβ. This mixture was placed in a 500774 autoclave reaction vessel. The sealed container was heated at 1/14° C. for 1 hour. The starting pressure was 17 Qpsi and the ending pressure was 180 rlsi. This mixture was cooled in uI L,
, evaporated to dryness under reduced pressure. The residue was dissolved in diethyl ether, filtered and concentrated under reduced pressure to give 5-methoxypyrimidine 23.4.0C yield 85
%) was obtained. The residue was recrystallized from hexane to obtain 17.88 fl of 5-methoxypyrimidine (yield: 65%). ml) = 45°C to 47°C Patent applicant: Eli Lilly & Company agent Patent attorney: Blue and white (1 person) 18-

Claims (1)

[Claims] 1. Formula (I) (wherein R1 is C1-C6 alkyl or phenyl, R
2 is -NH2, -Nl-ICHa, -N-(CH3)
2 or 01-C6 alkoxy, l represents 0-3) A method for producing a 5-substituted pyrimidine represented by the formula (■): (wherein, X is chloro or bromo, R1 and m
is the same meaning as above) is mixed with a suitable nuclear reagent under pressure in the presence of a sufficient amount of copper catalyst as a catalyst at about 0°C.
A method comprising reacting in the phlegm range of ~200<0>C for about 10 to about 90 minutes. 2. The method according to item 1, wherein R2 is -NH2. 3. The method according to item 1, wherein X is bromo. 4. The method according to item 1, wherein the copper catalyst is cupric sulfate. 5. The method according to item 1, wherein m is O. 6. The method according to item 5, wherein the compound of formula (I) is a 5-aminopyrimidine. 7. The method according to item 5, wherein the compound of formula (I) is N,N-dimethyl-5-pyrimidineamine. 8. The method according to paragraph 5, wherein the compound of formula (I>) is N-methyl-5-pyrimidineamine. 9. The method according to paragraph 5, wherein the compound of formula (I) is 2-[-butyl-5-aminopyrimidine]. The method according to item 5. 10. The method according to item 5, wherein the compound of formula (I) is 5-methoxypyrimidine.